Hospital Pharmacist Vol 7 No 1
p14-18
January 2000 Special Features
Thyroid disease
Treatment of thyroid diseases
By A. Bhattacharyya, DM, MRCP (UK) and H. M. Buckler, DM, FRCP
In the second article of our special feature, the authors describe the treatment options available for the various thyroid disorders. (The first article classifies the various diseases which could affect the proper functioning of the thyroid gland.)
The treatment of thyroid disease is relatively straightforward. True thyroid problems should be distinguished from sick euthyroid syndrome and due consideration should be given to the patient's age, gender, family and wishes in making treatment decisions.
Treatment of thyroid diseases falls into three main categories:
- Treatment of functional thyroid state, such as hypo- or hyperthyroidism
- Treatment of aetiology, as in thyroid carcinomas
- Treatment of goitre as a space-occupying lesion, ie, its effect on surrounding structures
Attention should also be paid to co-existing related illness, for example, treatment of Addison's disease with glucocorticoids, which can be associated with primary hypothyroidism or Graves' disease.
Primary hypothyroidism
The treatment of hypothyroidism was the first effective endocrine treatment. In the latter part of the nineteenth century, thyroid extract was tried and found to be beneficial. There is, perhaps, no experience more gratifying in clinical medicine than the response of the hypothyroid patient to appropriate therapy. Given a confirmed diagnosis, the treatment is thyroid hormone.
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Panel 1: Indications for the use of T3 over T4
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The daily requirement of thyroxine in adults varies between 50 and 200mcg, given as a single dose. The replacement is usually introduced gradually, especially in elderly patients and patients with co-existing ischaemic heart disease where there is a fear that treatment can worsen angina. It is our practice to start with a low dose (50mcg) in such situations.
The best way of monitoring response to treatment, in the case of primary hypothyroidism, is measurement of serum thyroid stimulating hormone (TSH). The TSH level should be maintained at the lower end of the normal range. It is important not to lower the TSH below the detectable range to avoid losing bone mass. This is very important because primary hypothyroidism is much more common in women in the peri- and postmenopausal period when they may be expected to lose bone (postmenopausal osteoporosis). In secondary and tertiary hypothyroidism, TSH cannot be relied upon and the free hormone (T4) should be measured. This will be discussed later.
Complications of T4 therapy are rare. The syndrome of pseudotumour cerebrie has been reported with initiation of treatment, particularly in children, that can worsen the visual fields.1 A gradual increase in the dose is required to avoid this situation. The other important aspect to consider when treating with T4 is the risk of precipitating acute adrenal crisis in patients with co-existing undetected primary or secondary hypoadrenalism. In this case, replacement therapy with glucocorticoid is mandatory prior to treatment with T4. As in most cases in clinical medicine where treatment is permanent, compliance is a problem. If education and family support are not successful, a large dose of T4, given once a week under supervision, seems to work reasonably well without causing side effects.2
Hyperthyroidism
The selection of appropriate therapy for the hyperthyroid patient depends on a diagnosis of hyperthyroidism and establishment of its cause. Treatment is influenced by age, sex, severity of symptoms, presence of associated illness, patient preference and the experience and background of the physician. Broadly, the treatment is divided into three categories: medical treatment, radioactive iodine (RAI) treatment and surgical removal of the thyroid gland.3
Medical treatment The main types of drug are shown in Panel 2. Currently, the two antithyroid drugs available are carbimazole (CMZ) and propylthiouracil (PTU). The serum half-life for CMZ and PTU are six to eight and one to three hours, respectively. CMZ has the benefit of a more prolonged biological effect and single dose therapy is usually sufficient. Carbimazole is usually started at a dose of 30-60mg daily and PTU at 100-200mg three times daily. As the patient shows clinical and biochemical improvement, the dose is reduced. This part of the treatment is more or less the same whatever the aetiology, be it Graves' disease, toxic multinodular goitre (MNG) or toxic adenoma.
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Panel 2: Mechanisms of actions of antithyroid drugs
Thionamides (CMZ and PTU): Inhibit organification of iodine and hence the synthesis of thyroid hormone. PTU also inhibits conversion of T4 to T3
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Antithyroid drugs are not without side effects, the commonest problem being skin rash. It is our practice to switch patients to PTU from CMZ if patients develop a rash with CMZ. The main serious complication is agranulocytosis, with a prevalence of 0.3-0.5 per cent.4 This is usually abrupt and not dose-related. Routine monitoring of blood count has not been shown to prevent this.5 Patients should be warned about the occurence of any infection, particularly sore throat. If this happens, they should stop the drug immediately and report to their own doctor or hospital for an urgent blood count. The other side effects are hepatitis, lupus syndrome, and arthritis.6
Beta adrenoceptor blocking drugs, or beta blockers, are used as conjunctive therapy. Propranolol is the drug of choice at 20-40mg two to four times daily. As the patient's symptoms improve, the dose is reduced and eventually the drug is stopped. Propranolol is also used in the pre-operative period to make the gland firmer. Lithium is used only rarely, when the patient cannot tolerate antithyroid drugs.7
Surgical and radioiodine treatment Definitive treatment after controlling the immediate symptoms of hyperthyroidism is mandatory for toxic MNG and toxic adenoma. RAI works well for both of them and is accepted almost universally. Some exceptions are where there are pressure symptoms from a big goitre or if cosmetic issues are important (particularly in young women). Iodine131 (I-131) is currently used at a dose of 600-800Mbq and the idea is to achieve a euthyroid state with the lowest possible risk of hypothyroidism.8,9 Rarely more than one dose is required to achieve the expected clinical response.
Surgery is not commonly used as a primary treatment of hyperthyroidism. Other than those mentioned above, the usual indications for surgery are: failure to respond to medical treatment, intolerance to antithyroid medications and a young age. A retrosternal goitre is a relative contraindication for RAI. A significant percentage of patients will develop overt hypothyroidism following RAI treatment. A very high level of thyroid microsomal antibody before operation has been correlated with the development of post-operative hypothyroidism.10 Percutaneous ethanol injection therapy, in particular with toxic adenoma, has been tried recently in some centres under ultrasound guidance with reasonable success.11
Iodine-induced hyperthyroidism is typically seen with long standing MNG or single nodule goitre in the residents of iodine-deficient areas who have received large doses of iodine in the form of a contrast agent. Iodine-induced hyperthyroidism is usually mild and self-limiting, but, rarely, can be serious and fatal. Beta blockers are useful. Anti-thyroid drugs, when used, require a higher dose. Heightened awareness on the part of health professionals is the most important way to avoid this situation.12
Thyroid cancers
The standard treatment for thyroid cancers is surgical removal of the thyroid gland followed by RAI (ablative dose) and lifelong T4 to suppress serum TSH. Poor prognostic factors in thyroid cancer are: histological type (undifferentiated thyroid cancer, medullary thyroid cancer, follicular thyroid cancer), tumour size greater than 5cm, invasive tumour and old age. (See panel 3).
Panel 3: AGES Clarification for prognosis of thyroid cancer19A Age of the patient |
There is no consensus as to whether subtotal or complete thyroidectomy is necessary for treating patients with thyroid cancer, although there is a general view that partial thyroidectomy or lumpectomy is an inadequate operation. One of the reasons for differing opinions about the treatment of patients with papillary thyroid cancer is that about 80 per cent will do well, regardless of how they are treated. Also, more extensive thyroid resection is associated with a higher complication rate.13 The advantages of total thyroidectomy include the removal of all intrathyroid tumours and the ability to follow up with thyroglobulin. After definitive surgical treatment of differentiated thyroid cancer, the decision whether or not to ablate any remaining tissue must be made. Older patients (aged over 40 years) with follicular cancer or occult papillary cancer, younger patients (below 20 years) with papillary or follicular cancer and patients of any age with known residual tumour, known metastatic disease or recurrent disease, are candidates for an ablative dose of I-131. Medullary and anaplastic cancers do not concentrate I-131, hence there is no role for ablation. Ablation treatment is given four to six weeks after withdrawal of T3 and T4, so that a rise in TSH will increase I-131 uptake. Measurement of thyroglobulin is helpful for remnant disease or metastases. Serum calcitonin measurements are extremely helpful in following up medullary thyroid carcinoma. Following I-131 ablation and failure to find extra thyroidal uptake, the patient is placed on thyroid hormone therapy and the dose should suppress serum TSH to undetectable levels. A repeat scan is usually not performed if the ablation is successful, thyroglobulin level is normal and recurrent disease is not evident. I-131 ablation is also the treatment of choice for metastatic thyroid cancer. Chemotherapy has been disappointing in the treatment of thyroid cancer.
Thyroid nodules
Problems associated with nodular goitre are: obstructive symptoms, hypothyroidism, hyperthyroidism and malignancy. In young patients, cosmetic appearance is a particular concern. All of these should be taken into consideration in the treatment. Radioactive iodine treatment or antithyroid drugs do not reduce the size of the goitre significantly. Thyroxine has been tried in younger patients with euthyroid goitre but the success rate is not encouraging. If there is any doubt, histological diagnosis should be aimed to rule out malignancy.
Special situations
Thyroid disease can arise in special situations, or be secondary to other disease states. The rest of the article discusses the treatment for each situation.
Thyroid diseases in pregnancy Thyroid disease is common in women. Women on T4 replacement therapy for primary hypothyroidism before pregnancy nearly always require incremental doses. In some centres, a 50 per cent increase in dose is instituted during the second and third trimester.14 Monitoring of free T4 is important, along with serum TSH, as total thyroxine level is normally raised in pregnancy.
Hyperthyroidism in pregnancy is more difficult to treat. In existing Graves' disease, patients should be advised to conceive either in remission or in a well controlled state with antithyroid drugs only. RAI is contraindicated during pregnancy.9 Where women are receiving RAI, they should not conceive for six months following treatment.
Graves' disease in pregnancy needs careful monitoring. A "block and replacement" regimen is clearly not acceptable in pregnancy as antithyroid drugs freely cross the placenta but T4 does not. Antithyroid drugs are the main stay of therapy. The only other option is surgical treatment. The dose should be as low as possible to keep the free T4 in the upper normal and serum TSH in the lower normal ranges.15 When it comes to choosing an antithyroid drug, most studies show that both PTU and CMZ can be used, although PTU is preferred, especially in the United States.16,17 The incidence of major congenital malformation in babies whose mothers were treated with PTU or CMZ does not differ.17
Due consideration should be given to the foetal thyroid state. The problems encountered are growth retardation, stillbirth and foetal Graves' disease. Foetal Graves' disease is suspected where there is growth retardation, goitre in the ultrasound scan and foetal tachycardia. It is treated by giving antithyroid drugs to the mother, as these drugs freely cross the placenta. If the mother is euthyroid, she should be given T4 to prevent the development of hyperthyroidism from antithyroid medication given for the foetus. Surgery is reserved for difficult situations. The main indications are intolerance to antithyroid medication and poor control of hyperthyroidism. The best time to offer subtotal thyroidectomy, if required, is the second trimester.
Thyroid medication and breast-feeding Mothers on T4 can breast-feed normally. However, there are concerns about breast-feeding while on antithyroid drugs. Propylthiouracil is usually preferred, as it is more protein-bound and secreted less in breast milk. However, the actual amount secreted in milk is very low. For example, in a mother taking 200mg PTU three times daily, the infant receives a mean dose of 99 mcg per day, ie, only 0.77 per cent of an ingested dose is excreted in the milk.18 Carbimazole in a dose of 15-20mg daily or PTU 150-200mg daily in divided doses (every dose taken immediately after the feed), is considered to be safe. Infants should be tested for thyroid dysfunction, however.
Thyroid diseases in children Both hypo- and hyperthyroidism in children should be treated promptly as they can affect the growth rate velocity. A catch-up growth is usually noted after treatment but it depends on the duration and severity of the dysfunction prior to the initiation of treatment. In hypothyroidism, the dose of T4 should be increased according to the body weight (recommended dose 5-8mcg per kg per day). Neonatal screening for congenital hypothyroidism has been implemented over the past 15-25 years and is successful in eradicating severe mental deficiency due to hypothyroidism. A higher initial dose of 10-15mcg per kg per day is used in such a situation.21
The treatment of choice for hyperthyroidism is antithyroid medication in the titration regimen. Surgery is the second line of choice in case of failed medical treatment. Radioactive iodine treatment in children is not popular. Due to its possible oncogenic potential, it is best avoided except for refractory cases, although the relation between RAI treatment, leukaemia and solid tumour is, at best, controversial.8,21 Thyroid carcinoma in the paediatric age group is uncommon and the line of treatment should be the same as in adults.
Thyroid diseases in the elderly Treatment of hypothyroidism in the elderly is no different from the standard as far as choice of drug is concerned. However, treatment should be instituted very slowly. It is our practice to increase the dose by 25mcg every four to six weeks. The diagnosis of hyperthyroidism is difficult in most patients as they present with atypical symptoms or signs.22 Both toxic MNG and Graves' disease are common in the elderly. Treatment with RAI is preferable in both situations although the dose requirement for MNG is usually higher.23 Thyroid diseases are more common in the elderly, although they are mostly benign. If a diagnosis of thyroid malignancy is made, treatment is still total thyroidectomy followed by RAI ablation and a suppressive dose of T4.
Amiodarone-induced thyroid diseases Amiodarone causes thyroid dysfunction by virtue of its high iodine content. It reduces the conversion of T4 to T3, and therefore a raised T4 and a lowered T3 level is a common biochemical abnormality in amiodarone-treated patients. In the diagnosis of amiodarone-induced hyperthyroidism, a combination of clinical features and a raised T3 is important.24,25 In addition, the long tissue half-life of amiodarone means that its effect can be prolonged for months after stopping the drug. Amiodarone is a preferred drug in cardiovascular practice. In most cases, stoppage of the drug is difficult because of poor co-morbid cardiac illnesses, but wherever possible it should be stopped. Amiodarone-induced hypothyroidism is relatively easy to treat with the corner-stone being T4 replacement. Amiodarone-induced hyperthyroidism is less easy to treat. If the drug cannot be stopped, a multi-pronged approach is currently recommended. This involves the combination of an antithyroid drug, beta blockers and, if necessary, steroids. In patients with increased interleukin-6, steroids can be used to suppress the inflammation of the thyroid gland.26 Radioactive iodine, as is to be expected, will be absorbed less in the thyroid gland because of increased amounts of iodine in the circulation. Subtotal thyroidectomy is an option, although most patients are poor candidates for general anaesthesia.27 In pregnant women using amiodarone during pregnancy, there is no known effects on the baby.28
Thyroiditis The main objective in the treatment of thyroiditis is achieving a functional thyroid state, although relief of symptoms, such as pain in subacute thyroiditis, needs due attention.
Acute, suppurative thyroiditis requires analgesia and parenteral antibiotics. In most cases, a fine needle aspiration is done to relieve the pressure and obtain a sample for culture and sensitivity.
Subacute thyroiditis may be associated with thyrotoxicosis, usually mild, due to the release of thyroid hormones. As the gland itself does not make more thyroid hormones, antithyroid drugs are less useful. A short course of propranolol (for inhibition of T4 to T3 conversion) and corticosteroids is satisfactory in most cases. Patients should be carefully followed as, in the long term, they may develop permanent primary hypothyroidism.
Treatment of Riedel's (chronic) thyroiditis is surgical, the goal being to relieve pressure symptoms. Despite the invasive nature of the disorder, recurrence after resection is rare and prognosis is generally favourable.
Thyroid crises In both extremes, thyroid crisis is an emergency. In thyrotoxic crisis, there are three main areas that need attention and Panel 4 gives an overview. The areas are:
The principles of treatment of hyperthyroidism are: inhibition of thyroid hormone synthesis, prevention of release of preformed hormone, inhibition of conversion of T4 to T3 and removal of T4 and T3 from the circulation if needed (plasmapheresis, plasma exchange, and dialysis). In every case, due attention should be given to long-term treatment of hyperthyroidism once the crisis is over.
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Panel 4: Treatment of thyrotoxic crisis
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Myxoedema is the most severe form of primary hypothyroidism. Treatment of myxoedema coma is shown in Panel 5. The brain and heart are usually most affected. Factors associated with a poor outcome are:
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Panel 5: Treatment of myxoedema coma
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With early initiation of treatment, mortality has been dramatically reduced from 60-70 per cent to 15-20 per cent.30,31 The treatment of choice is thyroid hormone replacement, maintenance of body temperature, hydration, oxygenation, correcting metabolic defects such as hyponatraemia, hypoglycaemia and hypotension and treatment of precipitating factors. Thyroid hormone is replaced by T4 or a mixture of T3 and T4 or T3 alone given by the oral or intravenous route. In most cases, the patients are unable to accept the medication orally and it is given by nasogastric tube and the absorption may be slow and erratic. Thyroxine can be given as an intravenous (IV) bolus dose of 300-500mcg, followed by 50 mcg IV daily until the patient can take it orally. A large amount of T4 is needed to saturate the empty binding sites. Whether there is an advantage of T3 over T4 is controversial. When T3 is preferred, it is given at a dose of 25mcg IV eight hourly for the first 48 hours, followed by an oral (or via naso-gastric tube) dose of 12.5-25mcg eight hourly until the patient is able to tolerate oral T4.
The rationale behind the combination of T4 and T3 is that T3 acts rapidly and exerts its effect before the effects of T4 are evident. However this has not been proved to be of benefit.32,33 Glucocorticoids are used if there is a suspicion of undiagnosed Addison's disease and the risk of precipitating an Addisonian crisis.
Secondary and tertiary hypo- and hyperthyroidism Treatment of secondary and tertiary hypothyroidism is not different from primary hyperthyroidism. When monitoring thyroid replacement, TSH cannot be relied upon. Free T4 is used in this instance. In a similar situation, replacement of other deficient hormones should be kept in mind, as isolated deficiency of TSH in hypothalamo-pituitary disorder is very rare.
Central hyperthyroidism is due to a TSH-secreting pituitary tumour or selective TSH resistance, both of which are rare. In the case of a TSH-secreting pituitary tumour (macroadenoma), hypophysectomy followed by external radiotherapy is the treatment of choice. Octreotide has a role in pre-operative preparation. Currently, there is no ideal treatment for selective pituitary resistant hyperthyroidism. The different treatments used are: antithyroid drugs, bromocriptine and T3.34 The goal of treatment is to control thyrotoxic symptoms rather than normalization of thyroid parameters.35
Subclinical thyroid diseases Patients with subclinical hypothyroidism may be at risk of increased atherogenicity. In the modern era of lipid awareness, there may be a case for treating such patients. Otherwise the rate of developing overt hypothyroidism in such patients (monitored by measuring serum TSH and free T4) is around 5 per cent.36
Subclinical hyperthyroidism is defined as undetectable serum TSH and normal serum thyroid hormone concentration. It should be distinguished from sick euthyroid syndrome and secondary and tertiary hypothyroidism. The two main reasons for treatment are increased incidence of atrial fibrillation and a decrease in bone mineral density.37,38
Pressure symptons of enlarged thyroid gland The main concerns are: pressure on the trachea (dyspnoea), recurrent laryngeal nerve (dysphonia) and oesophagus (dysphagia). A much more serious condition is retrosternal goitre, causing a severe pressure effect on vascular structures in the superior mediastinum. Early detection is the key to success. In hyperthyroidism with retrosternal goitre, RAI is a relative contraindication as, immediately after radiation exposure, the gland can enlarge and increase the obstruction. Surgery is the treatment of choice.
Thyroid eye disease The factors which govern the management of thyroid-associated eye disease are: visual acuity, rapidity and severity of eye symptoms, systemic thyroid status and involvement of extra-ocular muscles.
Fortunately, moderate to severe eye disease is uncommon. Initial management involves controlling the symptoms of hyperthyroidism. Patients should not be over-treated with antithyroid medication, as a raised TSH can aggravate ophthalmopathy. RAI is a relative contraindication, but recent studies showed no worsening when treated with prednisolone before RAI.39 Bedrest, eye protection (to prevent inadvertent injury to the eye during sleep), artificial tears, and a course of high dose corticosteroids are often used. Rarely, immunomodulatory agents such as cyclosporin are required.40 Surgical treatment is occasionally needed. Progressive proptosis with ocular inflammation and optic neuropathy with recent deterioration of visual acuity are the main indications for surgery.
Comment
In general, the treatment of thyroid disease is relatively simple. Prognosis is good as a rule. Before starting treatment, it is important to confirm the diagnosis (especially to rule out sick euthyroid syndrome). As already mentioned, in very few areas in medicine is the result of treatment as gratifying as in hypothyroidism. The recent rise in the incidence of thyroid cancers due to radiation exposure should always make us alert.